Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia.
Targeting BCL2 with Venetoclax in Relapsed Chronic Lymphocytic Leukemia.
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DOI：
10.1056/nejmoa1513257
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发表时间：
2016-01-28
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影响因子：
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通讯作者：
Seymour JF
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作者：
Roberts AW;Davids MS;Pagel JM;Kahl BS;Puvvada SD;Gerecitano JF;Kipps TJ;Anderson MA;Brown JR;Gressick L;Wong S;Dunbar M;Zhu M;Desai MB;Cerri E;Heitner Enschede S;Humerickhouse RA;Wierda WG;Seymour JF
新的治疗方法改善了复发性慢性淋巴细胞白血病（CLL）患者的预后，但完全缓解仍不常见。维奈托克具有独特的作用机制;它靶向BCL 2，一种对CLL细胞存活至关重要的蛋白质。我们在复发性或难治性CLL或小淋巴细胞淋巴瘤（SLL）患者中进行了每日口服维奈托克的I期剂量递增研究，以评估安全性、药代动力学特征和疗效。在剂量递增阶段，56例患者在8个剂量组之一中接受活性治疗，剂量范围为150 - 1200 mg/天。在扩展队列中，另外60例患者接受每周逐步递增剂量治疗，剂量高达400 mg/天。大多数研究患者接受过多次既往治疗，89%的患者具有预后不良的临床或遗传特征。维奈托克在所有剂量水平下均具有活性。在剂量递增队列中，56例患者中有3例发生临床肿瘤溶解综合征，1例死亡。在调整剂量递增方案后，扩展队列中的60例患者均未发生临床肿瘤溶解综合征。其他毒性反应包括轻度腹泻（52%的患者）、上呼吸道感染（48%）、恶心（47%）和3级或4级中性粒细胞减少（41%）。未确定最大耐受剂量。在接受venetoclax的116名患者中，92名（79%）有反应。在预后不良的亚组患者中，缓解率范围为71%至79%，包括对氟达拉滨耐药的患者、染色体17 p缺失（缺失17 p CLL）的患者和未突变IGHV的患者。20%的患者完全缓解，包括5%的患者在流式细胞术上没有微小残留病变。400 mg剂量组的15个月无进展生存率估计为69%。用维奈托克选择性靶向BCL 2具有可管理的安全性特征，并在复发性CLL或SLL患者（包括具有不良预后特征的患者）中诱导实质性缓解。（由AbbVie和Genentech资助; ClinicalTrials.gov编号，NCT 01328626。
New treatments have improved outcomes for patients with relapsed chronic lymphocytic leukemia (CLL), but complete remissions remain uncommon. Venetoclax has a distinct mechanism of action; it targets BCL2, a protein central to the survival of CLL cells. We conducted a phase 1 dose-escalation study of daily oral venetoclax in patients with relapsed or refractory CLL or small lymphocytic lymphoma (SLL) to assess safety, pharmacokinetic profile, and efficacy. In the dose-escalation phase, 56 patients received active treatment in one of eight dose groups that ranged from 150 to 1200 mg per day. In an expansion cohort, 60 additional patients were treated with a weekly stepwise ramp-up in doses as high as 400 mg per day. The majority of the study patients had received multiple previous treatments, and 89% had poor prognostic clinical or genetic features. Venetoclax was active at all dose levels. Clinical tumor lysis syndrome occurred in 3 of 56 patients in the dose-escalation cohort, with one death. After adjustments to the dose-escalation schedule, clinical tumor lysis syndrome did not occur in any of the 60 patients in the expansion cohort. Other toxic effects included mild diarrhea (in 52% of the patients), upper respiratory tract infection (in 48%), nausea (in 47%), and grade 3 or 4 neutropenia (in 41%). A maximum tolerated dose was not identified. Among the 116 patients who received venetoclax, 92 (79%) had a response. Response rates ranged from 71 to 79% among patients in subgroups with an adverse prognosis, including those with resistance to fludarabine, those with chromosome 17p deletions (deletion 17p CLL), and those with unmutated IGHV. Complete remissions occurred in 20% of the patients, including 5% who had no minimal residual disease on flow cytometry. The 15-month progression-free survival estimate for the 400-mg dose groups was 69%. Selective targeting of BCL2 with venetoclax had a manageable safety profile and induced substantial responses in patients with relapsed CLL or SLL, including those with poor prognostic features. (Funded by AbbVie and Genentech; ClinicalTrials.gov number, NCT01328626.)